CN117653610B - Nitroglycerin tablet and preparation method thereof - Google Patents
Nitroglycerin tablet and preparation method thereof Download PDFInfo
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- CN117653610B CN117653610B CN202311271764.XA CN202311271764A CN117653610B CN 117653610 B CN117653610 B CN 117653610B CN 202311271764 A CN202311271764 A CN 202311271764A CN 117653610 B CN117653610 B CN 117653610B
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- nitroglycerin
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- lophatherum gracile
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- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 239000000006 Nitroglycerin Substances 0.000 title claims abstract description 95
- 229960003711 glyceryl trinitrate Drugs 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 77
- 239000000203 mixture Substances 0.000 claims abstract description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 62
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 54
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 54
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 54
- 240000003915 Lophatherum gracile Species 0.000 claims abstract description 53
- 229920000881 Modified starch Polymers 0.000 claims abstract description 31
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims abstract description 31
- 235000013539 calcium stearate Nutrition 0.000 claims abstract description 31
- 239000008116 calcium stearate Substances 0.000 claims abstract description 31
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 31
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 31
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 30
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 30
- 229920001577 copolymer Polymers 0.000 claims abstract description 29
- 239000006185 dispersion Substances 0.000 claims abstract description 29
- 238000002156 mixing Methods 0.000 claims description 57
- 239000006228 supernatant Substances 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 27
- 239000011259 mixed solution Substances 0.000 claims description 24
- 239000002244 precipitate Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 19
- FJPHHBGPPJXISY-UHFFFAOYSA-N 2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCCC(C(O)=O)NC(=O)C(NC(=O)CNC(=O)CN)CC1=CC=C(O)C=C1 FJPHHBGPPJXISY-UHFFFAOYSA-N 0.000 claims description 12
- 108090000790 Enzymes Proteins 0.000 claims description 12
- 102000004190 Enzymes Human genes 0.000 claims description 12
- 108090000526 Papain Proteins 0.000 claims description 12
- 101710193050 Papain inhibitor Proteins 0.000 claims description 12
- 239000004365 Protease Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 229940088598 enzyme Drugs 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 229940055729 papain Drugs 0.000 claims description 12
- 235000019834 papain Nutrition 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 229940078456 calcium stearate Drugs 0.000 claims description 9
- 229960001866 silicon dioxide Drugs 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 230000001105 regulatory effect Effects 0.000 description 16
- 230000000750 progressive effect Effects 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 8
- 238000003287 bathing Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000691 measurement method Methods 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 229940075507 glyceryl monostearate Drugs 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a nitroglycerin tablet and a preparation method thereof, wherein the nitroglycerin tablet is composed of 1.3% -1.7% of nitroglycerin, 2% -5% of lophatherum gracile protein peptide mixture and/or 2% -5% of ethyl acrylate-methyl methacrylate copolymer water dispersion, 0.4% -0.7% of silicon dioxide, 10% -16% of pregelatinized starch, 0.4% -0.7% of calcium stearate and lactose monohydrate.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of a nitroglycerin tablet.
Background
The nitroglycerin (C 3H5N3O9) is used for treating and preventing coronary heart disease and angina pectoris, and is the earliest nitrate anti-angina pectoris medicament applied, so far, the nitroglycerin is still the more common medicament for treating acute angina pectoris. The administration route of the nitroglycerin is sublingual administration, and the nitroglycerin is absorbed by tongue mucosa, so that the nitroglycerin has quick response, can take effect in about 2 minutes, and can maintain the action time for 15-40 minutes. Nitroglycerin is not easy to swallow, and is not easy to absorb because the nitroglycerin can be destroyed in the gastrointestinal tract. The medicine is unstable and volatile, and can be easily moved from the tablet, and can be slowly decomposed when being heated, damped, exposed to sunlight or stored for a long time, the medicine effect can be reduced or failed, and the rescue effect is affected, so that the medicine should be protected from light, heat and moisture during storage.
Patent document CN 115154431A discloses a nitroglycerin tablet and a preparation method thereof, wherein the tablet comprises nitroglycerin as an active ingredient, and further comprises a stabilizer, a filler, a glidant, a disintegrating agent and a lubricant. Patent US6500456 discloses a formulation of nitroglycerin tablet and a preparation method thereof, using nitroglycerin, lactose, silicon dioxide, calcium stearate, starch and glyceryl monostearate as raw and auxiliary materials. The technology can solve the stability problem of the nitroglycerin tablet to a certain extent, and the quality of the product is relatively stable after the nitroglycerin tablet is placed for a period of time under the accelerated experimental condition. However, the stability is not satisfactory, the stability is relatively stable only in a short time, the content, uniformity and hardness are relatively little changed, and the impurity content is obviously improved. Accordingly, it would be desirable for the skilled artisan to provide a new nitroglycerin tablet manufacturing process to address the stability problem thereof.
Disclosure of Invention
In order to solve the technical problems, the invention provides a nitroglycerin tablet and a preparation method thereof.
The technical scheme of the invention is as follows:
the nitroglycerin tablet comprises the following raw materials in parts by mass:
1.3 to 1.7 percent of nitroglycerin, 2 to 5 percent of lophatherum gracile protein peptide mixture and/or 2 to 5 percent of ethyl acrylate-methyl methacrylate copolymer water dispersion, 0.4 to 0.7 percent of silicon dioxide, 10 to 16 percent of pregelatinized starch, 0.4 to 0.7 percent of calcium stearate and lactose monohydrate.
Preferably, the raw materials of the nitroglycerin tablet comprise: 1.3 to 1.7 percent of nitroglycerin, 2 to 5 percent of lophatherum gracile protein peptide mixture, 2 to 5 percent of ethyl acrylate-methyl methacrylate copolymer water dispersion, 0.4 to 0.7 percent of silicon dioxide, 10 to 16 percent of pregelatinized starch, 0.4 to 0.7 percent of calcium stearate and lactose monohydrate.
Preferably, the raw materials of the nitroglycerin tablet comprise: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and lactose monohydrate.
Preferably, the preparation method of the lophatherum gracile protein peptide mixture comprises the following steps of:
s1-1: mixing herba Lophatheri powder with water to obtain mixed solution, adjusting pH of the mixed solution to be 9.0-9.5, performing water bath at 50-60deg.C for 2-3 hr, centrifuging to obtain supernatant, adjusting pH to be 4.6-5.0, centrifuging, and collecting precipitate;
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution, adding papain, carrying out limited hydrolysis in a water bath with the enzyme dosage of 50-100U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 0.5-1h, centrifuging to obtain a supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
More preferably, the preparation method of the lophatherum gracile protein peptide mixture comprises the following steps of:
s1-1: mixing herba Lophatheri powder with water to obtain mixed solution, adjusting pH of the mixed solution to be 9.0-9.5, performing water bath at 60deg.C for 2 hr, centrifuging to obtain supernatant, adjusting pH to be 4.6-5.0, centrifuging, and collecting precipitate;
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor (a commercially available product is selected, CAS number is 70195-20-9) after enzymolysis for 1h, centrifuging to obtain a supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
Preferably, the preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating in a water bath at 95-100 ℃ for 60-90min, rapidly cooling to room temperature within 10 min (the composition conformation is influenced by rapid cooling, the mixture is more beneficial to improving the product stability after being mixed with the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion), adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%;
(2) Uniformly mixing the product obtained in the step (1), nitroglycerin, lactose monohydrate, silicon dioxide and calcium stearate to obtain a mixture, and tabletting by a tablet press to obtain the nitroglycerin tablet.
More preferably, the preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating in a water bath at 95-100 ℃ for 60min, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%;
(2) Uniformly mixing the product obtained in the step (1), nitroglycerin, lactose monohydrate, silicon dioxide and calcium stearate to obtain a mixture, and tabletting by a tablet press to obtain the nitroglycerin tablet.
Compared with the prior art, the invention has the beneficial effects that:
The nitroglycerin tablet provided by the invention has higher stability, stable content of functional components and lower content of impurities under the condition of high-temperature acceleration.
The preparation method provided by the invention is simple and convenient, is easy to operate, and is favorable for industrialized production of the high-stability nitroglycerin tablet.
Detailed Description
The present invention will be described in further detail with reference to the following specific embodiments, so that those skilled in the art can better understand the technical contents of the present invention.
Example 1 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 4% of glyceryl monostearate, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance lactose monohydrate.
The preparation method of the nitroglycerin tablet comprises the following steps:
Uniformly mixing nitroglycerin, lactose monohydrate, silicon dioxide, calcium stearate, glyceryl monostearate and pregelatinized starch (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, and tabletting by a tablet press to obtain the nitroglycerin tablet.
Example 2 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating in a water bath at 95-100 ℃ for 60min, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
Example 3 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of an aqueous ethyl acrylate-methyl methacrylate copolymer dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the nitroglycerin tablet comprises the following steps:
uniformly mixing nitroglycerin, lactose monohydrate, silicon dioxide, calcium stearate, ethyl acrylate-methyl methacrylate copolymer water dispersion and pregelatinized starch (uniformly mixing according to a conventional equal-amount progressive mode), obtaining a mixture, drying, and tabletting by a tablet press to obtain the nitroglycerin tablet.
Example 4 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating for 60min in a water bath at 100 ℃, rapidly cooling to room temperature within 10 min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
1. The nitroglycerin tablets prepared in each example were placed in a glass bottle and left at 60℃for a period of time, and the disintegration time, content and related substances were measured. The measurement method is carried out according to the measurement method under the "nitroglycerin tablet" item of Chinese pharmacopoeia of 2020 edition, and 10 batches of samples are measured in parallel.
TABLE 1
The results in Table 1 show that the nitroglycerin tablet prepared in example 2 has the best stability, and that the stability of the product of example 2 is significantly better than that of the other examples after 3 months of standing at higher temperature. Compared with example 3 and example 4, the stability of the product is obviously improved after the lophatherum gracile protein peptide mixture and the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion are added, which shows that the stability of the nitroglycerin tablet can be effectively improved by adding the components as auxiliary materials in the formula. The above components can significantly improve stability based on the replacement of the stabilizer glycerol monostearate.
2. The invention also particularly researches the influence of the preparation process on the stability of the product.
On the basis of example 2, a control group was designed. The control examples are as follows:
Comparative example 1:
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 500U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
Uniformly mixing raw materials such as nitroglycerin, lactose monohydrate, silicon dioxide, calcium stearate, lophatherum gracile protein peptide mixture, ethyl acrylate-methyl methacrylate copolymer water dispersion, pregelatinized starch and the like (uniformly mixing according to a conventional equal-amount progressive mode), obtaining a mixture, drying, and tabletting by a tablet press to obtain the nitroglycerin tablet.
Comparative example 2
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 500U/g and the temperature of 45-50 ℃, adding papain inhibitor after enzymolysis for 3 hours, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
Uniformly mixing raw materials such as nitroglycerin, lactose monohydrate, silicon dioxide, calcium stearate, lophatherum gracile protein peptide mixture, ethyl acrylate-methyl methacrylate copolymer water dispersion, pregelatinized starch and the like (uniformly mixing according to a conventional equal-amount progressive mode), obtaining a mixture, drying, and tabletting by a tablet press to obtain the nitroglycerin tablet.
The nitroglycerin tablets prepared in each comparative example were placed in a glass bottle and left at 60 ℃ for a period of time, and the disintegration time, content, and related substances were measured. The measurement method is carried out according to the measurement method under the "nitroglycerin tablet" item of Chinese pharmacopoeia of 2020 edition, and 10 batches of samples are measured in parallel.
TABLE 2
Example 2 by mixing Lophatherum gracile protein peptide and pregelatinized starch at 100deg.C, covalently bonding protein peptide group with starch group, rapidly cooling, adding ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, and mixing to form viscous film composition, thereby protecting nitroglycerin and improving high temperature stability of nitroglycerin.
As is clear from the results of comparative example 2, the degree of enzymolysis of the lophatherum gracile protein peptide also has a significant effect on the stability of the final product, and excessive enzymolysis of example 2 may be disadvantageous for subsequent improvement of the product stability.
The present invention also provides the following examples to illustrate the most reasonable process parameter ranges found by the present invention. Within the following reasonable range, after the accelerated test at 60 ℃ for 3 months, the disintegration time limit is less than 50s, and the requirement of Chinese pharmacopoeia is met within 2 minutes. The content is not changed significantly, and the content of related substances is lower than 0.7%.
Example 5 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.3% of nitroglycerin, 5% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 16% of pregelatinized starch, 0.7% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating for 60min in a water bath at 100 ℃, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing, stirring for at least 20min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
Example 6 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.7% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 5% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.7% of silicon dioxide, 10% of pregelatinized starch, 0.4% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating for 60min in a water bath at 100 ℃, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing, stirring for at least 20min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
Example 7 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
S1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 50deg.C for 3 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 100U/g and the temperature of 45-50 ℃, adding papain inhibitor after enzymolysis for 0.5h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating for 60min in a water bath at 100 ℃, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing, stirring for at least 20min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
Example 8 preparation method of nitroglycerin tablet
The formula of the product comprises the following steps: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and the balance of lactose monohydrate.
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water at a mass ratio of 1:10 to obtain a mixed solution, regulating pH of the mixed solution to 9.0-9.5 with sodium hydroxide solution, water-bathing at 60deg.C for 2 hr, centrifuging to obtain supernatant, regulating pH of the supernatant to 4.6-5.0 with hydrochloric acid solution, centrifuging, and collecting precipitate.
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating for 90min in a water bath at 95 ℃, rapidly cooling to room temperature within 10min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%.
(2) Uniformly mixing the product obtained in the step (1), the nitroglycerin, the lactose monohydrate, the silicon dioxide and the calcium stearate (uniformly mixing according to a conventional equal-amount progressive mode) to obtain a mixture, drying, and tabletting by a tabletting machine to obtain the nitroglycerin tablets.
The foregoing description is only exemplary embodiments of the invention and is not intended to limit the invention thereto. All modifications, equivalents, and alternatives falling within the spirit and principles of the invention are intended to fall within the scope of the invention.
Claims (4)
1. The nitroglycerin tablet is characterized by comprising the following raw materials in parts by mass: 1.3 to 1.7 percent of nitroglycerin, 2 to 5 percent of lophatherum gracile protein peptide mixture, 2 to 5 percent of ethyl acrylate-methyl methacrylate copolymer water dispersion, 0.4 to 0.7 percent of silicon dioxide, 10 to 16 percent of pregelatinized starch, 0.4 to 0.7 percent of calcium stearate and lactose monohydrate;
The preparation method of the lophatherum gracile protein peptide mixture comprises the following steps of:
S1-1: mixing herba Lophatheri powder with water to obtain mixed solution, adjusting pH of the mixed solution to be 9.0-9.5, performing water bath at 50-60deg.C for 2-3 hr, centrifuging to obtain supernatant, adjusting pH to be 4.6-5.0, centrifuging, and collecting precipitate;
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution, adding papain, carrying out limited hydrolysis in a water bath with the enzyme dosage of 50-100U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 0.5-1h, centrifuging to obtain a supernatant, and freeze-drying to obtain a lophatherum gracile protein peptide mixture;
The preparation method of the nitroglycerin tablet comprises the following steps:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating in a water bath at 95-100 ℃ for 60-90 min, rapidly cooling to room temperature within 10min, adding an ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%;
(2) Uniformly mixing the product obtained in the step (1), nitroglycerin, lactose monohydrate, silicon dioxide and calcium stearate to obtain a mixture, and tabletting by a tablet press to obtain the nitroglycerin tablet.
2. The nitroglycerin tablet according to claim 1, wherein the raw materials and auxiliary materials thereof comprise: 1.5% of nitroglycerin, 2% of lophatherum gracile protein peptide mixture, 2% of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, 0.4% of silicon dioxide, 15% of pregelatinized starch, 0.6% of calcium stearate and lactose monohydrate.
3. The nitroglycerin tablet according to claim 1, wherein the method for preparing the lophatherum gracile protein peptide mixture comprises the following steps:
s1-1: mixing herba Lophatheri powder with water to obtain mixed solution, adjusting pH of the mixed solution to be 9.0-9.5, performing water bath at 60deg.C for 2 hr, centrifuging to obtain supernatant, adjusting pH to be 4.6-5.0, centrifuging, and collecting precipitate;
S1-2: adding water into the precipitate obtained in the step S1-1 to prepare a solution with the mass concentration of 10% -15%, adding papain, carrying out limited hydrolysis in a water bath with the enzyme amount of 50U/g and the temperature of 45-50 ℃, adding a papain inhibitor after enzymolysis for 1h, centrifuging, taking supernatant, and freeze-drying to obtain the lophatherum gracile protein peptide mixture.
4. The nitroglycerin tablet according to claim 1, wherein the preparation method of the nitroglycerin tablet comprises the steps of:
(1) Dissolving the lophatherum gracile protein peptide mixture into water according to the mass concentration of 3% -5%, adding pregelatinized starch, stirring, mixing and heating in a water bath at 95-100 ℃ for 60min, rapidly cooling to room temperature within 10 min, adding the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, mixing and stirring for at least 20min, and concentrating to enable the water content to be 10% -20%;
(2) Uniformly mixing the product obtained in the step (1), nitroglycerin, lactose monohydrate, silicon dioxide and calcium stearate to obtain a mixture, and tabletting by a tablet press to obtain the nitroglycerin tablet.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IL61721A (en) * | 1980-12-16 | 1984-03-30 | Blank Izhak | Nitroglycerin preparations |
| JP3242324B2 (en) * | 1996-04-08 | 2001-12-25 | ニチバン株式会社 | Nitroglycerin transdermal preparation |
| IL134395A (en) * | 1997-10-03 | 2005-08-31 | Warner Lambert Co | Compressed nitrogylycerin tablet and its method of manufacture |
| US20030206942A1 (en) * | 1998-09-25 | 2003-11-06 | Neema Kulkarni | Fast dissolving orally consumable films containing an antitussive and a mucosa coating agent |
| RU2005129309A (en) * | 2003-05-02 | 2006-05-10 | Уорнер-Ламберт Компани Эл-Эл-Си (US) | SUITABLE FOR ORAL USE FAST SOLUBLE FILMS CONTAINING MODIFIED STARCH FOR IMPROVED HEAT AND MOISTURE RESISTANCE |
| CN1829490A (en) * | 2003-07-01 | 2006-09-06 | 托德·迈巴赫 | Films comprising therapeutic agents |
| ITMI20050477A1 (en) * | 2005-03-23 | 2006-09-24 | Bouty S P A | TRANSDERMIC PATCH |
| CN110278998A (en) * | 2017-02-18 | 2019-09-27 | 武汉华康臣生物科技有限公司 | A kind of purslane leaf protein special medicine purposes formula food |
| CN110591390B (en) * | 2019-09-19 | 2021-09-17 | 广东工业大学 | Dialdehyde starch crosslinked fiber/cottonseed protein composite material and preparation method and application thereof |
| CN114831950B (en) * | 2022-04-29 | 2023-05-05 | 广州新济药业科技有限公司 | Nitroglycerin coating, nitroglycerin sublingual tablet and preparation method thereof |
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| Title |
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| 硝酸甘油口服控释制剂的研究;买尔旦;《北京医科大学学报》;19960418;第28卷(第2期);143-144, 147 * |
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